Disintegrating particle composition produced by two-stage wet granulation process, and intraorally disintegrating tablet containing same composition

ABSTRACT

A method is used in the production of a disintegrative particulate composition including three components consisting of a first disintegrator component having sedimentation volume in water of 4.0 cm3/g or more, and a second disintegrator component other than the first disintegrator component and an excipient. The method includes a first wet granulation step using any two of the three components, and a second wet granulation step using the granules obtained in the first wet granulation step and at least the component not used in the first wet granulation step; thus the disintegrative particulate composition is produced. Moreover, an orally disintegrating tablet contains a medicinal ingredient and the disintegrative particulate composition.

This application is a Divisional of U.S. application Ser. No.15/021,647, filed Mar. 11, 2016, which claims priority to InternationalPatent Application No. PCT/JP2014/075241, filed Sep. 24, 2014, whichclaims priority to Japanese patent Application No. 2013-202248, filedSep. 27, 2013. The entirety of the aforementioned applications isincorporated herein by reference.

FIELD

The present invention relates to a disintegrative particulatecomposition produced by a two-stage granulation process, an orallydisintegrating tablet comprising said composition and the like.

BACKGROUND

In the past, orally disintegrating tablets have been developed as highlyconvenient forms which can safely be taken by patients who havedifficulty in swallowing drugs, elderly people, children, etc., andwhich can easily be taken without water. In addition to the need by saidpeople, the need for the orally disintegrating tablets has beenincreased in the field of health food products, for example, in thesituation where the convenience of taking without water can be utilizedsuch as a supplement tablet for athletes during exercise. It isimportant, that the orally disintegrating tablets have sufficientbreaking strength (tablet hardness) such that any cracks, powdering,etc. are not caused in the tablets during production or transportationof the tablets or during breaking their seals in the same manner asgeneral tablets, and also, it is important that the orallydisintegrating tablets have excellent disintegrability (disintegrationtime) such that the tablets immediately disintegrate in the oral cavity.

An excellent moldability will be required in the production of a tablet.The moldability means the relation between a tablet compression forceand the tablet hardness obtained thereby. A process that needs a hightablet compression force could cause problems such as limitation in theperformance of a tablet-compressing machine, reduction of productivityand reduction in the properties of coating particles comprised in thetablet. It will be therefore important for the particle or particulatecomposition constituting the tablet to have such an excellentmoldability that a higher tablet hardness can be obtained with the sametablet compression force, or that the same tablet hardness can beobtained by a lower tablet compression force.

The tablet hardness and disintegrability are mutually opposingproperties. In general, when a molding pressure is increased to increasethe hardness, the disintegration time will tend to be prolonged, and,when the molding pressure is reduced to shorten the disintegration time,the hardness will tend to be smaller. Therefore, various technologieshave been developed in order to cope with both the two properties or toachieve an optimal balance between the two properties. Furthermore, thecomponents of particles, granulation methods, etc. have been studied inorder to impart superior moldability to the particles or particulatecompositions constituting tablets.

For example, Patent Literature (PTL) 1 discloses a disintegrativeparticulate composition that is produced by homogeneously dispersingmannitol, xylitol, inorganic excipient, disintegrator and carmellose inthe presence of water, followed by drying. The composition ischaracterized in that xylitol is solid-dispersed in mannitol particlesto form composite particles, and that inorganic excipient, disintegratorand carmellose are dispersed in the composite particles. Saiddisintegrative particulate composition is produced by spray-granulationof the dispersion wherein the above components are dispersed in aqueoussolvent or by spraying to carriers made of mannitol and the like.

PTL 2 discloses an orally disintegrating tablet comprisingcarboxymethylcellulose in an amount of 10% (w/w) or more based on thetotal amount including medicinal ingredients. It is produced by mixingeach component, followed by formulation with a tableting machine.

PTL 3 discloses a method for the production of an orally disintegratingtablet comprising loratadine as a medicinal ingredient. The methodinclude two granulation steps, wherein loratadine is granulated with atleast one of additives such as a binder, excipient, disintegrator andthe like in a first granulation step, and the resulting granulesobtained in the first granulation step is further granulated with atleast one of the same additives as in the first step. Carmellose islisted as an example of the disintegrator.

Furthermore, PTL 4 discloses a method for the production of an orallydisintegrating tablet. The method comprises a step of spraying anaqueous suspension of a water-soluble and hydrophilic disintegrator ontoa mixture of a medicinal ingredient and an excipient to give a granulate(A) comprising the medicinal ingredient, and a step of spraying anaqueous suspension of the same water-soluble and hydrophilicdisintegrator as above onto the excipient to give a granulate (B)without the medicinal ingredient, and a step of compression molding ofthe granulates (A) and (B).

RELATED ARTS Patent Literatures

PTL 1: International Publication Pamphlet WO2011/019045

PTL 2: JP-A-2008-285434

PTL 3: JP-A-2012-31138

PTL 4: Specification of Japanese Patent No. 4551627

SUMMARY

The problems to be solved by the present invention is to provide amethod for the production of a disintegrative particulate compositioncomprising first and second integrator components, which can provide anorally disintegrating tablet with the composition with both an excellenttablet hardness and disintegrability when it is added to the orallydisintegrating tablet.

Means to Solve the Problem

The present inventors have earnestly studied and found that the aboveproblems can be solved by using a method for the production of adisintegrative particulate composition including three componentsconsisting of a first disintegrator component having sedimentationvolume in water of 4.0 cm3/g or more, a second disintegrator componentother than the first disintegrator component and an excipient, whichcomprises a first wet granulation step using any two of the threecomponents and a second wet granulation step using the granules obtainedin the first wet granulation step and at least the remaining onecomponent not used in the first wet granulation step.

Thus, the present invention relates to the following aspects.

Aspect 1

A method for the production of a disintegrative particulate compositionincluding three components consisting of a first disintegrator componenthaving sedimentation volume in water of 4.0 cm³/g or more, a seconddisintegrator component other than the first disintegrator component andan excipient, which comprises a first wet granulation step using any twoof the three components and a second wet granulation step using thegranules obtained in the first wet granulation step and at least theremaining one component not used in the first wet granulation step.

Aspect 2

The method according to Aspect 1, wherein the first disintegratorcomponent is crospovidone, croscarmellose sodium, carboxymethyl starchsodium, carboxymethylcellulose calcium, α-starch or partially α-starch.

Aspect 3

The method according to Aspect 2, wherein the first disintegratorcomponent is crospovidone.

Aspect 4

The method according to one of Aspects 1 to 3, wherein the seconddisintegrator components are one or more of non-α-starch, corn starch,processed starch, hydroxypropyl starch and low substitutedhydroxypropylcellulose.

Aspect 5

The method according to one of Aspects 1 to 4, wherein crystallinecellulose is used as a forth component in the first wet granulation stepand/or the second wet granulation step.

Aspect 6

A disintegrative particulate composition produced by the methodaccording to one of Aspects 1 to 5.

Aspect 7

An orally disintegrating tablet comprising a medicinal ingredient andthe disintegrative particulate composition according to aspect 6.

Advantageous Effects of Invention

By producing a disintegrative particulate composition including threecomponents consisting of a first disintegrator component havingsedimentation volume in water of 4.0 cm³/g or more, a seconddisintegrator component other than the first disintegrator component andan excipient according to a method that comprises particular two steps,it is possible to produce a disintegrative particulate composition thatprovides more excellent tablet hardness and disintegrability than thoseof the disintegrative particulate composition including the samecomponents but produced by a method using said three components togetherin one granulation step.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows tablet hardness and disintegration time in water of eachtablet obtained in Examples and Comparative Examples.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the method for the production of thedisintegrative particulate composition including three componentsconsisting of the first disintegrator component having sedimentationvolume in water of 4.0 cm3/g or more, the second disintegrator componentother than the first disintegrator component and the excipient, which ischaracterized by comprising the first wet granulation step using any twoof the three components and the second wet granulation step using thegranules obtained in the first wet granulation step and at least theremaining one component not used in the first wet granulation step. Thesecond wet granulation step may use the granules obtained in the firstwet granulation step and only the remaining one component not used inthe first wet granulation step.

Four mechanisms of “wicking”, “swelling”, “deformation” and “repulsion”have been proposed as mechanisms of disintegration of tablets or thelike. Among them, “swelling” is a disintegration mechanism whichproceeds upon swelling of disintegrators themselves as a result of waterpermeation through the disintegrators.

The first disintegrator component included in the disintegrativeparticulate composition according to the present invention ischaracterized by having sedimentation volume in water of 4.0 cm³/g ormore. The sedimentation volume in water of the disintegrator componentis a value determined according to the following method.

Method for the Determination of Sedimentation Volume in Water

A disintegrator component (1.0 g) was gradually added to a beakercontaining s purified water of 75 mL while being stirred with a stirrer.After the completion of addition of the whole volume of thedisintegrator component, it is stirred for 3 min. The resultingsuspension is then transferred to a measuring cylinder (100 mL), dilutedin the measuring cylinder to 100 mL, and allowed to stand still for 16hours, followed by measuring the sedimentation volume.

Values of the sedimentation volume determined by the above method areshown in Table 1 for representative examples of the disintegratorcomponents. As the sedimentation volume of the disintegrator componentis correlated with its swelling property, it is estimated that thelarger is the sedimentation volume of the disintegrator component, thehigher is its swelling property.

Thus, it is preferable to use as the first disintegrator component onethat is high in swelling property, that is, superior in the effect ofpromoting swelling. Preferable examples of such disintegrator componentinclude crospovidone, croscarmellose sodium, carboxymethyl starchsodium, carboxymethylcellulose calcium, alpha-starch or partiallyalpha-starch. Crospovidone, which is a popular name of a cross-linkedpolymer of 1-vinyl-2-pyrrolidone, is more preferable. Croscarmellosesodium is a popular name for a cross-liked product ofcarboxymethylcellulose sodium.

As the second disintegrator component are listed one or more ofnon-alpha-starch, corn starch, processed starch, hydroxypropyl starchand low substituted hydroxypropylcellulose.

Acid-type carboxymethylcellulose is a substance called carmellose. Insome cases, a salt of carboxymethylcellulose may be referred to ascarmellose. Although such carmellose is included in some of theconventional tablets as the disintegrator, it is preferable not to beincluded in the disintegrative particulate composition according to thepresent invention.

Table 1 shows the sedimentation volumes (swelling property) in water ofthe representative examples of the disintegrator components, which weredetermined by the above method.

TABLE 1 Sedimentation Volume Disintegrator Component in Water (cm³/g)Corn starch 1.5 Hydroxypropyl starch 1.5 Carmellose 2.5 Crospovidone 6.0Croscarmellose sodium 14 Carboxymethyl starch sodium 26Carboxymethylcellulose calcium 9.5 Alpha-starch 14 Partiallyalpha-starch 8.0

Any compound which has been known to those skilled in the art as anexcipient may be included as the third component in the disintegrativeparticulate composition of the present invention. Typical examples ofsuch a compound include sugars or sugar alcohols such as mannitol,erythritol, sorbitol, D-glucitol (maltitol), xylitol, trehalose, lactoseand maltose. Moreover, as preferable examples thereof, mannitol,erythritol, trehalose, sorbitol and D-glucitol (maltitol) can bementioned. As the excipient, two or more types of compounds properlyselected from these compounds can also be used. Furthermore, whenexcipients are used in each of the first and second wet granulationsteps, the excipients may be of the same type (the same combination), ormay be of different types (different combinations).

The disintegrative particulate composition produced by the method of thepresent invention can include a crystalline cellulose known to thoseskilled in the art, as the fourth component. As typical examples of sucha crystalline cellulose, commercially-available products such as“Avicel” (FMC Corporation), “CEOLUS” (Asahi Kasei Chemicals Corp.), and“VIVAPUR” (RETTENMAIER) can be mentioned.

Furthermore, various types of optional components known to those skilledin the art may properly be added and mixed into the disintegrativeparticulate composition of the present invention, for the purpose ofadjusting various characteristics such as the disintegrating force,binding force and ease in taking the tablet, without impairing theeffects of the present invention according to the above-described threeor four components. As examples of such components, fluidizing agents,inorganic excipients, sweetening agents, flavoring agents and coloringagents can be mentioned.

The amount of each component blended in the disintegrative particulatecomposition of the present invention can properly be determined by thoseskilled in the art, depending on, for example, the type of thecomponent, the type and purpose of the medicinal ingredient, which is atarget to be used in the disintegrative particulate composition, or thepurpose of the final product, i.e. the orally-disintegrating tablet. Ingeneral, relative to the total weight of the disintegrative particulatecomposition, the amount of the first disintegrator component is within arange of 1% to 30% by weight, the amount of the second disintegratorcomponent is within a range of 1% to 30% by weight, and the amount ofthe excipient is within a range of 40% to 98% by weight, which are atotal amount used in the first and/or second wet granulation steps.

The first and second granulation steps of the method according to thepresent invention are carried out by a method in which each component isdispersed in the presence of water, and the dispersion is dried to formcomplexes, i.e. by a wet granulation process. As specific examples ofthe wet granulation process, spray methods such as spray drying,tumbling granulation, agitation granulation and fluidized-bedgranulation, the freeze-drying method, kneading granulation, and thelike can be mentioned, and the composition can be produced by any ofthese methods known to a person skilled in the art.

Since disintegrators are generally hydrophilic, by carrying out amanipulation of applying a physical force such as by agitation or thelike in the presence of water according to wet granulation, theaggregated state in the dry powder converts into a state in whichparticles are more dispersed. Dispersion can most easily be carried outby the fluidized-bed granulation process, spray drying, tumblinggranulation, agitation granulation, etc., in which dispersion by waterspraying and drying are carried out, and also, drying speeds in thesemethods are high. Therefore, these methods are preferable.

Among them, the fluidized-bed granulation process is a granulationmethod in which water, an aqueous solution including a binder, or thelike is sprayed onto powder, while blowing the powder up by hot air,and, for example, adjustment of spraying conditions, etc. is easy inthis method. Therefore, the fluidized-bed granulation process is themost preferable method.

Those skilled in the art can properly determine which two types of thecomponents among the three components are used in the first wetgranulation step of the present, depending on their types, amounts, etc.For example, the first wet granulation step can be carried out by usingone of the first or second disintegrator component, and the excipient,and the other disintegrator component can be added in the second wetgranulation step. Alternatively, the first wet granulation step can becarried out by using both the first and second disintegrator components,and the excipient can be added in the second wet granulation step. Thecrystalline cellulose can be optionally added in the first and/or secondwet granulation step.

Various types of the optional components, other than the above-describedcomponents, which can be appropriately included in the disintegrativeparticulate composition of the present invention and which have beenknown to those skilled in the art, may be properly added in the firstand/or second wet granulation step. Alternatively, these optionalcomponents may also be added and mixed in an appropriate granulationstep of the third step or subsequent steps.

Furthermore, those skilled in the art can properly determine variousconditions such as the spraying speed, the supply air temperature, theexhaust temperature, and the air supply rate, depending on types oramounts of components, etc.

In both of the first wet granulation step and the second wet granulationstep according to the fluidized-bed granulation process, as a medium forthe spray liquid, a solvent acceptable in pharmaceuticals or foods, suchas water, ethanol, methanol or acetone, can be mentioned. Alternatively,as the spray liquid, for example, an aqueous solution in which less than10% of the component(s) for the disintegrative particulate compositionis dissolved can be mentioned, and, in particular, water or such anaqueous solution is preferable.

The present invention relates also to the disintegrative particulatecomposition obtained by the method according to the present invention,and to the orally disintegrating tablet comprising a medicinalingredient and said disintegrative particulate composition. The orallydisintegrating tablet according to the present invention may optionallyinclude other components acceptable as additives from a pharmaceuticalor food-sanitary point of view, such as excipients, surfactants,lubricants, acidulants, sweeteners, corrigents, flavoring agents,colorants, and stabilizing agents, when needed. As these optionalcomponents, for example, appropriate ingredients described in “JapanesePharmaceutical Excipients Directory” (YAKUJI NIPPO LIMITED) or theJapanese Pharmacopoeia; designated or existing additives according toFood Sanitation Law, Art. 10; natural flavor; and additives listed in alist of general additives for food and drink can be used. There is nolimitation in the kind of the medicinal ingredient and the aboveauxiliary agents. Also, the blending ratios of the disintegrativeparticulate composition, the medicinal ingredient and each optionalingredient (component) are not particularly limited as long as theexpected effects of the present invention are brought about, and theblending ratios can properly be determined by those skilled in the art.The orally disintegrating tablet can be formulated by any methods knownto those skilled in the art, for example, by tableting.

It is preferable that the disintegrative particulate composition of thepresent invention have the following physical properties:

(1) an average particle size of 70 to 110 microns; and

(2) a water content of 2% to 6% by weight.

In addition, these physical properties are measured by using thefollowing methods and conditions.

The average particle size: 2 g of the disintegrative particulatecomposition is subjected to a measurement with a Φ75 mm automaticshaking sieve device (Type “M-2”, Tsutsui Scientific Instruments Co.,Ltd.).

The water content: 5 g of the disintegrative particulate composition issubjected to a measurement using a halogen water content measuringdevice (Type “HB43”, METTLER TOLEDO K.K.).

The orally-disintegrating tablet of the present invention may have ahardness of 50 to 150 N and a disintegration time in water of 10 to 60seconds, preferably have 80 to 150 N and a disintegration time in waterof 10 to 30 seconds.

In addition, contents of all related art documents cited in the presentspecification are incorporated herein by reference.

Hereinafter, the present invention will more specifically be describedwith reference to Examples. However, the present invention is notconsidered to be limited to the Examples.

EXAMPLES Example 1

As the first wet granulation step, 285 g of mannitol (D-mannitol, MerckLtd.), 75 g of cornstarch (an official drug included in JapanesePharmacopoeia; NIHON SHOKUHIN KAKO CO., LTD.) and 100 g of a crystallinecellulose (CEOLUS PH-101, Asahi Kasei Chemicals Corp.) were charged to afluidized-bed granulator (FL-LABO, Freund Corporation), and 150 g ofpurified water was sprayed onto the resulting mixture at a rate of5^(˜)15 g/minute to thereby granulate the mixture. Further, as thesecond wet granulation step, 40 g of crospovidone (Polyplasdone INF-10,ISP Japan) was added to the resulting granules, and 80 g of purifiedwater was sprayed thereto at 4 g/minute to thereby obtain granules (adisintegrative particulate composition of the present invention). 0.5parts by weight of magnesium stearate (Taihei Chemical Industrial Co.Ltd.) was added to 99.5 parts by weight of the obtained granules, andthese were mixed. The mixture was then subjected to tableting at tabletcompression forces of 6.0, 8.0 and 10.0 kN with a simple tabletingmachine (HANDTAB-100, ICHIHASHI-SEIKI Co., Ltd.) to thereby obtain anangled-corner flat tablet having a diameter of 8.0 mm and a weight of250 mg. In addition, the granules had the following values for physicalproperties: (1) an average particle size of 89 microns and (2) a watercontent of 3.4% by weight.

Example 2

As the first wet granulation step, 224 g of mannitol (D-mannitol, MerckLtd.), 80 g of hydroxypropyl starch (HPS-101W, Freund Corporation) and80 g of the crystalline cellulose (CEOLUS PH-101, Asahi Kasei ChemicalsCorp.) were charged to the fluidized-bed granulator (FL-LABO, FreundCorporation), and 120 g of purified water was sprayed onto the resultingmixture at a rate of 5 g/minute to thereby granulate the mixture.Further, as the second wet granulation step, 16 g of crospovidone(Polyplasdone INF-10, ISP Japan) was added to the resulting granules,and 80 g of purified water was sprayed thereto at 2^(˜)5 g/minute tothereby obtain granules (a disintegrative particulate composition of thepresent invention). The resulting granules were subjected to tabletingin the same manner as in Example 1 to thereby obtain an angled-cornerflat tablet having a diameter of 8.0 mm and a weight of 250 mg. Inaddition, the granules had the following values for physical properties:(1) an average particle size of 84 microns and (2) a water content of3.5% by weight.

Comparative Example 1

As the first wet granulation step, 285 g of mannitol (D-mannitol, MerckLtd.), 75 g of corn starch (official drug included in JapanesePharmacopoeia; NIHON SHOKUHIN KAKO CO., LTD.), 100 g of the crystallinecellulose (CEOLUS PH-101, Asahi Kasei Chemicals Corp.) and 40 g ofcrospovidone (Polyplasdone INF-10, ISP Japan) were charged to thefluidized-bed granulator (FL-LABO, Freund Corporation), and 80 g ofpurified water was sprayed onto the resulting mixture at a rate of 4g/minute to thereby obtain granules. The resulting granules weresubjected to tableting in the same manner as in Example 1 to therebyobtain an angled-corner flat tablet having a diameter of 8.0 mm and aweight of 250 mg. In addition, the granules had the following values forphysical properties: (1) an average particle size of 70 microns and (2)a water content of 3.8% by weight.

Comparative Example 2

As the first wet granulation step, 224 g of mannitol (D-mannitol, MerckLtd.), 80 g of hydroxypropyl starch (HPS-101W, Freund Corporation), 80 gof the crystalline cellulose (CEOLUS PH-101, Asahi Kasei ChemicalsCorp.) and 16 g of crospovidone (Polyplasdone INF-10, ISP Japan) werecharged to the fluidized-bed granulator (FL-LABO, Freund Corporation),and 80 g of purified water was sprayed onto the resulting mixture at arate of 4.6 g/minute to thereby obtain granules. The resulting granuleswere subjected to tableting in the same manner as in Example 1 tothereby obtain an angled-corner flat tablet having a diameter of 8.0 mmand a weight of 250 mg. In addition, the granules had the followingvalues for physical properties: (1) an average particle size of 88microns and (2) a water content of 3.7% by weight.

[Evaluation on Hardness and Disintegrability Tests]

Hardness and disintegrability of the tablets obtained in Examples andComparative Examples were measured by following methods. The testresults of hardness and disintegration time are shown in Table 2 andFIG. 1.

The values of the physical properties of the resulting tablets weremeasured based on the following conditions/methods.

Hardness: a hardness (N) was measured with a digital Kiya hardnesstester (Fujiwara Scientific Company Co., Ltd.).

Disintegration time in water: a disintegration time in water wasmeasured with a disintegration tester (NT-400, TOYAMA SANGYO CO., LTD.)in accordance with the method described in the Japanese Pharmacopoeiaprovided that an auxiliary disk was not used.

The measurements for the hardness and disintegration time were eachrepeated six times, and average values thereof were regarded asmeasurement results.

TABLE 2 Comparative Tablet Example 1 Example 1 Tablet Compression Force6.0 8.0 10.0 6.0 8.0 10.0 (kN) Tablet Hardness (N) 83 109 133 76 96 116Disintegration Time in 23 31 33 26 32 35 Water(s) Comparative TabletExample 2 Example 2 Tablet Compression Force 6.0 8.0 10.0 6.0 8.0 10.0(kN) Tablet Hardness (N) 86 106 129 78 101 119 Disintegration Time in 2732 37 30 35 38 Water(s)

The results shown in Table 2 demonstrate that the orally disintegratingtablet produced by the two-stage granulation process in Example 1 hasmore excellent disintegrability in spite of a high tablet hardness whencompared with that produced in Comparative Example (one-stagegranulation process).

The same results are obtained in Example 2 and Comparative Example 2.

INDUSTRIAL APPLICABILITY

The present invention significantly contributes to research anddevelopment of orally disintegrating tablets having excellent tablethardness and disintegrability.

1-7. (canceled)
 8. A disintegrative particulate composition includingthree components consisting of (1) a first disintegrator componenthaving sedimentation volume in water of 4.0 cm³/g or more, (2) a seconddisintegrator component other than the first disintegrator component,wherein the second disintegrator component is not an acid-typecarboxymethylcellulose, and (3) an excipient component, saiddisintegrative particulate composition is produced by a methodcomprising: a first wet granulation step using any two of the threecomponents; and a second wet granulation step using at least thegranules obtained in the first wet granulation step and the other one ofthe three components which is not used in the first wet granulationstep, wherein the first disintegrator component is crospovidone,croscarmellose sodium, carboxymethyl starch sodium,carboxymethylcellulose calcium, or alpha-starch or partiallyalpha-starch.
 9. The disintegrative particulate composition of claim 8,wherein the first disintegrator component is crospovidone.
 10. Adisintegrative particulate composition including three componentsconsisting of (1) a first disintegrator component having sedimentationvolume in water of 4.0 cm³/g or more, (2) a second disintegratorcomponent other than the first disintegrator component, wherein thesecond disintegrator component is not an acid-typecarboxylmethylcellulose, and (3) an excipient component, saiddisintegrative particulate composition is produced by a methodcomprising: a first wet granulation step using any two of the threecomponents; and a second wet granulation step using at least thegranules obtained in the first wet granulation step and the other one ofthe three components which is not used in the first wet granulationstep, wherein the second disintegrator components are one or more ofnon-alpha-starch, corn starch, processed starch, hydroxypropyl starchand low substituted hydroxypropylcellulose.
 11. A disintegrativeparticulate composition including three components consisting of (1) afirst disintegrator component having sedimentation volume in water of4.0 cm³/g or more, (2) a second disintegrator component other than thefirst disintegrator component, wherein the second disintegratorcomponent is not an acid-type carboxylmethylcellulose, and (3) anexcipient component, said disintegrative particulate composition isproduced by a method comprising a first wet granulation step using anytwo of the three components; and a second wet granulation step using atleast the granules obtained in the first wet granulation step and theother one of the three components which is not used in the first wetgranulation step, wherein crystalline cellulose is used as a fourthcomponent in the first wet granulation step and/or the second wetgranulation step.